At a major press conference this week, the Bill & Melinda Gates Foundation and 13 drugmakers, along with the World Bank, the US, Britain, and UAE, announced a joint effort to attack 10 neglected tropical diseases. The drug companies will be contributing $785 million to this effort and Gates is pledging $363 million to try to eliminate these diseases in the next decade. This is indeed a noble initiative, one that should be applauded for its ambition and scope. It will involve not just money and medicines, but also the talents of scientists at these companies who will help guide the critical research needed to make breakthroughs in eradicating these diseases. The fact that so many organizations are working together for the first time should help drive the success of this initiative.

But, for the pharmaceutical companies involved, this isn’t something new.

For decades, pharmaceutical companies have been working on programs designed to help people in the developing world. In 1987, Merck began efforts to eradicate river blindness, a disease spread by black fly bites and characterized by disfiguring dermatitis and eye lesions leading to loss of sight. Merck formed a partnership with the World Bank, the WHO, UNICEF and various ministries of health to provide free Mectizan (Ivermectin), which treats river blindness with a single annual dose, to anyone who needs it. More than 69 million Mectizan treatments are given each year across 33 different African and South American countries. The WHO estimates that 40,000 cases are prevented annually as a result of this program.

The Merck example is not unique. Zithromax (azithromycin) is a great drug to treat Chlamyida trachomatis, the bacterium responsible for causing trachoma and the leading cause of preventable blindness in the world. In 1998, Pfizer co-founded the International Trachoma Initiative (ITI) and, through the ITI, has provided over 54 million treatments of Zithromax to trachoma patients in 15 countries. This program is part of the WHO’s SAFE (Surgery, Antibiotics, Face-washing and Environmental improvement) strategy, which is designed to eradicate trachoma by 2020.

Virtually, every major pharmaceutical company has been involved in these types of efforts. GSK, AstraZeneca, Lilly, Sanofi-aventis and Novartis are all working to combat tuberculosis. Similarly, Pfizer, GSK, Novartis, Eisai and Sanofi-aventis are all working on malaria. The same can be said for AIDS and tropical diseases. In fact, the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) lists on its website 213 different efforts aimed at improving the plight of those suffering in the developing world.

Moreover, pharmaceutical companies historically have led all businesses in terms of generosity. In her Forbes article entitled “America’s Most Generous Companies” (October 10, 2010), Jacquelyn Smith reported that in 2009, according to The Chronicle of Philanthropy, six of the top 10 corporations were pharmaceutical companies. Pfizer led the list with $2.3 billion donated in total cash and product-giving. The top 10 also included Merck, Johnson & Johnson, Abbott, Lilly and Bristol-Myers Squibb.

There are cynics who will say that pharmaceutical companies are only doing this to help their image. The fact is that the companies have been doing this for so long that it is part of their culture. The men and women in these companies who help in these type of projects take great pride in this work. This new public-private partnership to combat 10 neglected diseases is a terrific initiative and hopefully will be met with great success. But for pharmaceutical companies, it is a continuation of decades of work and billions of dollars of investments.

One of the more interesting aspects of having a blog is getting comments from readers. It is always nice to get responses that enjoy the posts or that value my views. Of course, there are also some that suggest I don’t know what I’m talking about. I received one such comment last week which I believe merits a considered response. A couple of weeks ago, I wrote a piece entitled: “Disease Creep or Good Medical Practice?” Essentially, I was challenging the view that the use of statins to lower LDL cholesterol is an example of “disease creep” – the conversion of a risk-factor to an actual disease. Briefly, my view is that high cholesterol, while not a disease itself, is a strong predictor of heart disease in people with multiple cardiovascular risk factors and thus needs to be treated if diet and exercise aren’t sufficient to lower LDL cholesterol to recommended levels.

A few days later, I received a comment that began: “Did none of you receive the message that statin use was associated with the onset of type 2 diabetes?” The writer was referring to recent data from the Women’s Health Initiative (WHI) reported in the online edition of “Archives of Internal Medicine.” The investigation included 153,840 post-menopausal women aged 50 – 79 who were not diabetic at the start of the study. Over the course of the next 6 – 7 years, 10,242 women developed type 2 diabetes. After taking into account factors like lack of exercise and weight gain, it was determined by the WHI researchers that those on statins were 48% more likely to become diabetic than those not on statins at all.

Does this mean that statins can make older women more susceptible to diabetes? That is hard to say. It is possible that statins have effects on muscles and the liver that cause improper glucose metabolism, which could lead to diabetes. However, the WHI study is an observational study, not a prospective one and there are uncontrolled factors in an observational study. For example, women on statins may feel that they are protected from heart disease and may be eating more starches and sugars. Post-menopausal women don’t metabolize sugars well and this may be contributing to the increase in incidences of diabetes seen in this study.

Observational studies can yield wildly different results. Some, like the WHI study suggest negative effects of statins, others show unexpected benefits. It is interesting to note that a recent observational study suggests that taking statins may prevent death from flu. In a study entitled “Association Between Use of Statins and Mortality Among Patients Hospitalized With Laboratory-Confirmed Influenza Virus Infection: A Multistate Study” published in The Journal of Infectious Diseases (January 1, 2012), the authors reviewed the records of 3,043 older adults hospitalized with the flu in 2007/2008. Those who were on statins were 41% less likely to die from the flu over 30 days compared to those who weren’t, independent of age or flu vaccination status. An accompanying editorial to this article stated the dilemma that all observational studies pose: while there is a scientific rationale as to why statins could reduce mortality, the results might also be explained by a “healthy user bias” in that “statin users are more apt to be discriminating users of healthcare.” The editorial emphasized the need for a double-blind, placebo-controlled randomized trial of acute statin therapy in hospitalized statin-naïve, influenza infected patients to provide a definitive answer as to whether statins have protective benefits in flu patients.

Randomized prospective studies do exist for statins in diabetics. One of note is CARDS (Collaborative Atorvastatin Diabetes Study). CARDS was designed as a 6-year study and was made up of 2838 diabetes patients aged 40 – 75 with no history of heart disease. The patients were randomized to receive 10mg of atorvastatin or placebo. Over time, the LDL cholesterol levels of those on placebo remained unchanged (at about 120mg/dL, whereas those on atorvastatin had dropped to 77mg/dL on average. Surprisingly, the Data Safety Monitoring Board (DSMB) halted CARDS after only 4 years when it was found that those on atorvastatin had 35% fewer cardiovascular events, 48% fewer strokes and a death rate lowering of 27%. When the results of CARDS were reported in The Lancet (Vol. 364, 685 – 696, 2004), the authors concluded: “The debate about whether all patients with type 2 diabetes warrant statin treatment should now focus on whether any patients can reliably be identified as being at sufficiently low risk for this safe and efficacious treatment to be withheld.”

So statins can clearly benefit type 2 diabetics, but yet there is a concern that statins may predispose older women to diabetes. How should healthcare providers deal with this? My recommendation remains unchanged. If people have elevated LDL cholesterol levels, they should first try to control this with diet and exercise. If that is insufficient AND they have multiple cardiovascular disease risk factors (obesity, high blood pressure, family history, etc.), they should get their cholesterol down to American Heart Association recommended levels with a statin.

Statins are important drugs. But like any drug, they can have risks and need to be used appropriately.

In 2011, the FDA approved 30 New Medical Entities (NMEs) filed either as New Drug Applications (NDAs – small molecules) or Original Biologic License Applications (BLAs – therapeutic biologics). This is the largest number of approvals since 36 new drugs were approved in 2004. Furthermore, on average only 23 new drugs were approved in the previous decade, so the 2011 total is pretty impressive. People are debating whether this represents a turnaround for the biopharmaceutical industry or a one year aberration. Regardless, as good as 2011 was, there is no doubt that the number of new drugs produced by the industry is significantly lower than what it produced in the 1990s.

When people talk about this issue, they always use 1996 as their starting point. In that year, the FDA approved 53 NMEs, an all-time high. However, using the 1996 data as a starting point for a productivity discussion is totally inappropriate as THAT was a one year aberration. In the early 1990s, the U.S. was undergoing a “drug lag,” that is, drugs were being approved more rapidly abroad than in the U.S. As a result, a number of drugs were languishing at the FDA for years before approval. Needless to say, Congress got involved and they realized that the FDA was under-resourced to approve drugs in a timely fashion. To solve this problem, Congress enacted the Prescription Drug User Fee Act (PDUFA), a mechanism whereby charges were levied on pharmaceutical companies for each new drug application filed. The revenues from these “user fees” were used to hire 600 new drug reviewers and support staff. This personnel increase enabled the FDA to work through the backlog of NDAs. The record number of NDA approvals in 1996 is a result of this.

(As an aside, the user fee in 1995 for a full NDA was $208,000. In 2012, the fee is $1,841,500. Considering that fewer NDAs are being filed, given the nine-fold increase in PDUFA user fees, one might wonder why all drugs can’t be approved with a six months review time.)

Nevertheless, the FDA approved 315 new drugs from 1991 – 2000. Thus, despite the progress in technologies for drug discovery and development, as well as the wealth of information that has emanated from the Human Genome Project, the number of new drugs emerging annually has dropped significantly. What may account for this? For one thing, due to industry consolidation, there are fewer companies producing new drug candidates. In 1988, the Pharmaceutical Research and Manufacturing Association (PhRMA) had 42 members. Only 11 of those companies exist today. While there are biotech companies like Amgen that have arisen over this timeframe, there haven’t been nearly enough new companies formed that could make up for this decrease in NDA-producing organizations. Back in 1990, if a new idea for treating cancer arose, 25 different companies would have jumped on it. Given the challenges inherent in R&D, one might assume that 4 or 5 of these companies would have been successful in getting such a drug approved. Things are quite different now. With fewer companies competing, the chances for success drop precipitously. Not only are there then fewer NDAs produced, you also wind up getting fewer entrants in a new class of drugs, which provides fewer choices to patients, physicians and payers.

Another reason for the decrease in NDA output is the result of the higher safety and differentiation hurdles experimental medicines face. For a new drug to be a commercial success these days, it needs to be differentiated from existing therapies. In addition, the FDA is requiring that new compounds are effective in treating the disease itself and not just impact markers of the disease. For example, a new compound that lowers LDL (“bad”) cholesterol might be of value, but the FDA now requires data actually showing that such an agent actually reduces heart attacks in a patient population with cardiovascular disease. In the 1990s, simply lowering LDL was enough to get FDA approval. Outcomes studies, if they were done at all, would be done after the drug was approved and marketed. Now, extensive clinical trials are needed and the new agent not only has to reduce heart attacks and strokes, it also needs to do so better than the generic statins.

The impact on industry productivity as a result of higher differentiation and efficacy hurdles can be seen in the decrease in compounds clearing late stage (Phase 3) clinical studies. In the 1990s, >90% of compounds entering Phase 3 received FDA approval. Data from Arrowsmith (Nature Reviews Drug Discovery Vol. 10, 87, February 2011) suggests that only 50% of compounds entering Phase 3 get FDA approval. Phase 3, which prior to 2000 served to confirm results from early smaller scale clinical trials, now is a major hurdle in determining a drug’s ultimate medical and commercial value. The drugs that emerge from such vigorous trials are likely to be major advances. However, fewer of these occurrences happen now than a decade ago.

For NDA approvals, the 1990s can be viewed as an era when there were many large organizations producing multiple compounds that didn’t need to be differentiated from existing therapy nor show multiple year safety and disease reduction in patients. The rules, however, have changed. The hurdles and costs for new drug development are higher than ever before. As a result, to expect the industry to produce 50 new drugs per year is unrealistic, regardless of technology advances. Thirty is the new 50.

A brief article in The Economic Times (January 2, 2012) entitled “Zydus, Eli Lilly drug discovery deal off” got very little notice, but may represent a new trend. Three years ago, the Indian company Zydus Cadila signed a research pact with Lilly to collaborate on novel drugs to treat cardiometabolic disorders. The deal had the potential to be worth up to $300 million if Zydus Cadila achieved specific milestones and compounds passed key steps in clinical development. While not a lot of information was given for the dissolution of this collaboration, I found the following comment interesting:

“Developing a new drug from scratch is getting more expensive due to increased regulatory scrutiny and high costs of clinical trials. Lowering costs through a partnership with an Indian drug firm was one way of speeding up the process, but the success rate has not been very high.”

Much has been made of the growing investment in R&D being made by Western pharmaceutical companies in places like China and India. Initially, this work was meant as a way to get laboratory work done more cheaply. However, about a decade ago, Western companies turned to their outsourcing partners to tap into their scientific talent and to broaden their search for new medicines. This blended well with the ambitions of these countries to become bigger players in the lucrative global pharmaceutical market. A few years ago, this trend was discussed by Pete Engardio and Ben Rissing in a Business Week story entitled “Big Pharma’s R&D Booster Shot” (June 11, 2008) which focused on India and highlighted the proliferation of deals, such as India’s Glenmark Pharmaceuticals liaison with Lilly and Ranbaxy’s drug-discovery alliance with Merck. The authors acknowledged that, while Indian firms were unlikely to compete in the development of new medicines overnight due to the long drug discovery-development timeline, they were clearly on the path to be eventual competitors.

But the Indian firms are now discovering how difficult this business is. The Zydus Cadila – Lilly example is not unique. Similar disappointing stories can be told for the early diabetes drugs that Dr. Reddy’s Laboratories licensed to Novo Nordisk and Novartis, or Glenmark’s anti-asthmatic compound that was licensed to Forest Laboratories. However, these setbacks shouldn’t be thought of as a failing of India’s nascent pharmaceutical efforts. They just provide further evidence of how challenging drug discovery is, no matter where it is done.

However, there could be at least one concern with India’s emerging drug pipeline. In his article “India Perseveres as Drug Discoverer” (Chemical & Engineering News, October 31st, 2011), Amruthanand Nair shows a table listing the drug candidates in advanced development from several major Indian firms, including Dr. Reddy’s, Glenmark, Piramal Life Sciences and Sun Pharma. Of the 10 compounds listed, many are mechanistically related to agents that are already on the market or they are in classes where previous compounds have had little or no success. It is hard to imagine that any of these agents will be blockbusters without long-term and expensive clinical studies that would differentiate them from current therapies. Do these small companies have the internal resources to carry out such studies? If not, they will need a major pharma partner to do this. And this comes back to the “developing a new drug from scratch” quote above. It is entirely possible that, as happened with the Zydus Cadila – Lilly deal, Western partners will be dissolving these deals unless there is compelling evidence that the compounds generated will meet not just regulatory scrutiny but also the very high hurdle that now exists for compound differentiation.

When it comes to drug discovery, the Indian pharmaceutical industry is still in its infancy. It will be awhile before the “eventual competitor” status will be realized.

The American Heart Association has been monitoring deaths due to cardiovascular disease (CVD) in the U.S. for over a century. While the CVD death rate grew steadily for most of the 20th century, it leveled off and then began to drop somewhat over the past 25 years. Nevertheless, CVD is still the leading cause of death in the U.S. with 600,000 people dying annually, which accounts for more than 25% of all deaths in the country. The direct costs associated with treating heart disease amount to over $80 billion/year and indirect costs attributed to loss of productivity exceed $60 billion/year.

Despite the progress made in moderating the CVD death rate, it is still a major disease. Furthermore, as the obesity epidemic continues in the U.S., recent headway is liable to be counteracted by the increase in obesity, which is already resulting into a concomitant increase in type 2 diabetes, a precursor to heart disease. Even with improvements in diagnosis and treatment, better understanding of risk factors, reductions in smoking, etc., CVD is going to remain a major health problem for decades.

Diet and exercise are keys to staying healthy, not just to ward off heart disease and diabetes but other diseases as well. Yet, there are times when medical treatment becomes a necessary add-on to preventing heart attacks and strokes. It is not a coincidence that the lowering of CVD deaths occured at the advent of statins such as Zocor (simvastatin) and Lipitor (atorvastatin), drugs that lower LDL cholesterol which is a key factor in the formation of atherosclerosis. These medicines have been shown to be both effective and safe for long-term use.

“Elevated cholesterol is not a disease. It doesn’t cause symptoms. It is a risk factor. People with high cholesterol levels are somewhat more likely to develop a heart attack or stroke, but they are at far less risk than individuals who already have cardiovascular disease. This is the definition of disease creep: when pre-conditions or risk-factors are treated as if they are the same as the actual disease state.”

In Lenzer’s utopia, you wouldn’t get a statin until AFTER you have already had a heart attack. The problem is that many first heart attacks are fatal – you don’t get a second chance to go on statin therapy then. She is correct in saying that just having high cholesterol alone does not justify taking a statin to prevent a heart attack or stroke. But CVD risk factors also include male sex, older age, family history of heart disease, post-menopause, smoking, obesity, high blood pressure, diabetes and stress. If a patient presents to a physician with multiple risk factors and if diet and exercise have not been effective in lowering cholesterol levels to those recommended by the American Heart Association, that physician would be remiss if the patient wasn’t prescribed a statin. Waiting for a patient to first have a heart attack or stroke before providing such treatment would be irresponsible.

Lenzen implies in her article that the prophylactic use of statins may only prevent 1 in 50 heart attacks. I don’t necessarily agree with that number, but let’s say that is correct. There are 785,000 first heart attacks/year in the U.S. Even employing Lenzen’s assumptions, the use of statins in the overall treatment paradigm of patients with multiple CVD risk factors would prevent thousands of heart attacks or strokes annually. Now that the most-studied statins like simvastatin and atorvastatin are generic, it would seem like the cost-benefit of statin use to prevent first heart attacks is non-controversial. This isn’t “Disease Creep” – it is simply good medical practice.

To most working in pharmaceutical R&D, it became clear a decade ago that the era of novel anti-hypertensive research was coming to a close. The blood pressure market was saturated with many safe and effective drugs, most of which were generic or soon to be so. These treatments included diuretics, beta blockers, alpha blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Thus, it was pretty surprising that Novartis pursued renin inhibition, yet another type of mechanism for blood pressure lowering. This approach was not novel. In fact, scientists had been working on trying to discover and develop novel renin inhibitors since the early 1980s. For a variety of reasons, most companies had abandoned their efforts by 2000 as it was no longer clear that a renin inhibitor would have any benefit over existing therapies.

Thus, it was pretty surprising that Novartis continued in this field and brought aliskerin (sold as Tekturna or Rasilez) to market in 2007. The fact that Novartis scientists were able to find such an agent after decades of research in an area where many had failed was remarkable. Aliskerin was indeed a potent blood pressure lower. It significantly lowered blood pressure for a full 24 hours when given as a single dose and added efficacy when dosed on top of other blood pressure medications. But its blood pressure lowering effects weren’t dramatically better than existing therapies. Was aliskerin too late to market for it to be a commercial success? Renin is an enzyme that initiates the first step in what is called the “renin-angiotensin (RAS) cascade” that ultimately produces the blood pressure regulating peptide angiotensin 2. But the ACE inhibitors and ARBs both also target the RAS cascade, so many questioned whether aliskerin would offer meaningful advantages over existing agents. Why would payers be willing to pay a premium price for a new unproven agent without superiority data?

Novartis tried to show the medical importance of aliskerin by conducting a number of long-term outcomes studies to demonstrate its advantages. One of these was called ALTITUDE (ALiskerin Trial In Type 2 Diabetics nEphropathy). Novartis described the trial as follows:

“The placebo-controlled Phase 3 ALTITUDE study is the first trial to investigate Rasilez/Tekturna for more than one year in a specific population of patients with type 2 diabetes and renal impairment. These patients are known to be at high risk of cardiovascular and renal events. In the study, Rasilez/Tekturna was given in addition to optimal cardiovascular treatment including an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).”

ALTITUDE was an events driven study involving 8,600 patients and it was monitored by an independent Data Safety Monitoring Board (DSMB). Novartis was hoping to show that aliskerin, when added to conventional therapy, delayed heart and kidney complications in the type 2 diabetes population. Basically, Novartis hoped that in addition to lowering blood pressure aliskerin would also have protective effects for organs like the kidney. In studies like this, it is the role of the DSMB to monitor the progress of patients on a periodic basis in order to determine how well the novel treatment is working.

On December 20, Novartis announced that the DSMB recommended that the ALTITUDE study be halted. To great surprise, they found that the trial arm that contained aliskerin after 18 – 24 months resulted in an INCREASED incidence of non-fatal stokes, renal complications, hyperkalemia and hypotension in this high risk study population. As a result, Novartis immediately halted promotion of aliskerin-based products for use in combination with ACE inhibitors or ARBs. For some unknown reason, aliskerin doesn’t seem to have organ protective properties, but its use appears to cause unforeseen toxicities when given in combination with other blood pressure lowering medications.

This is a terrible result for Novartis and is likely to cause the demise of this drug. Matthew Herper’s Forbes story on this event contained the following quote from Texas cardiologist Dr. John Osborne, who summarizes the situation that Novartis now faces:

“The Novartis hypertension franchise is now DOA, obviously. Furthermore, this class of DRIs has died with the death of this drug… Furthermore, given this data, why would one use this molecule anyway?”

A few lessons can be drawn from this.

1) Going after a new mechanism where there are already excellent treatments on the market is always very risky, especially when generics are already present or on the horizon. This isn’t limited to anti-hypertensives. For example, an area like LDL-cholesterol lowering is very well-served with statins. Any new LDL-lowering agent would have to be very special for payers and physicians to accept it. The same thing can be said for anti-histamines, anti-ulcer agents, etc. R&D resources are best spent in areas of major medical need, where a new medicine can make a difference.

2) If you still believe your new drug has something to offer patients, despite the fact that good medicines already exist in this therapeutic area, it behooves you to do key clinical studies before filing the NDA. My guess is that, despite the fact that Novartis has generated income over the past 4 years with aliskerin, the R&D, manufacturing and launch costs for this drug were pretty high and not compensated for the sales to date.

3) This type of result further supports conservatism by regulatory authorities. I wouldn’t be surprised if the FDA uses this case as an example of why they want more Phase 3 studies carried out BEFORE approval in order to justify registration of a new drug in a therapeutic area already well served.

When a drug fails, it is not an event that impacts only one company. Presumably, other R&D organizations will learn from this and design future clinical development programs appropriately. For regulatory agencies, one would hope that this type of result won’t cause further conservatism and cause them to increase the demands placed upon companies charged with the discovery and development of new medicines. Finally, this is another example that can be used to teach the critics of the drug industry that the work pharma does is challenging and highly risky – yet important to the health of us all.